Bottom Line:
Mitophagy is a selective form of macro-autophagy in which mitochondria are selectively targeted for degradation in autophagolysosomes.Mitophagy can have the beneficial effect of eliminating old and/or damaged mitochondria, thus maintaining the integrity of the mitochondrial pool.The challenges and opportunities that come with our heightened understanding of the role of mitophagy in cancer are reviewed here.

Affiliation: The Ben May Department for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, IL 60637 USA ; The Committee on Cancer Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637 USA.

ABSTRACTMitophagy is a selective form of macro-autophagy in which mitochondria are selectively targeted for degradation in autophagolysosomes. Mitophagy can have the beneficial effect of eliminating old and/or damaged mitochondria, thus maintaining the integrity of the mitochondrial pool. However, mitophagy is not only limited to the turnover of dysfunctional mitochondria but also promotes reduction of overall mitochondrial mass in response to certain stresses, such as hypoxia and nutrient starvation. This prevents generation of reactive oxygen species and conserves valuable nutrients (such as oxygen) from being consumed inefficiently, thereby promoting cellular survival under conditions of energetic stress. The failure to properly modulate mitochondrial turnover in response to oncogenic stresses has been implicated both positively and negatively in tumorigenesis, while the potential of targeting mitophagy specifically as opposed to autophagy in general as a therapeutic strategy remains to be explored. The challenges and opportunities that come with our heightened understanding of the role of mitophagy in cancer are reviewed here.

Fig2: BNIP/NIX promotes mitophagy through direct interaction with LC3 at the phagophore. BNIP3 and NIX are both hypoxia-inducible genes that encode molecular adaptors that promote mitophagy through interaction with processed LC3-related molecules at nascent phagophores (A). Both BNIP3 and NIX interact with Bcl-2 and Bcl-XL through their amino terminal ends, and Bcl-2/Bcl-XL has been postulated to play both positive and negative regulatory effects on BNIP3 function (A). BNip3 has also been shown to interact with regulators of mitochondrial fission (Drp-1) and mitochondrial fusion (Opa-1). These interactions are positive and negative, respectively, resulting in a role for BNIP3 in promoting fission while inhibiting fusion (B). BNIP3 has also been shown to interact with the small GTPase, Rheb, resulting in reduced Rheb activity, reduced mTOR activity, and reduced cell growth (C). This function for BNIP3 in modulating Rheb (C) contrasts with the proposed functional interaction of NIX with Rheb (D) that elicits a mTOR-independent effect on mitophagy by promoting LC3 processing and increased mitochondrial turnover in cells grown on oxidative substrates (D). NIX is required for recruitment of Rheb to mitochondria and its activating effect on mitophagy.

Mentions:
BNIP3 and NIX integrate into the OMM as redox-resistant homo-dimers with a short 10 to 11 amino acid carboxy terminal tail in the intermembrane space and a proximal 23 amino acid transmembrane domain containing a critical glycine zipper that is required for both dimerization and membrane integration [69-71]. The remaining amino terminal portion of both BNIP3 and NIX protrudes out into the cytosol where both BNIP3 and NIX interact with LC3-related molecules at associated phagophore membranes [72,73] (Figure 2A). The direct interaction of BNIP3 and NIX with processed LC3B-II or GABARAP is dependent on a LC3-interacting region (LIR) located within an unstructured amino terminal region of each protein (amino acids 15 to 21 in BNIP3 and 43 to 49 in NIX) [72-74], and thus, similar to ATG32 in yeast [75,76], BNIP3 and NIX function to target mitochondria directly to the autophagosome for degradation. Binding of BNIP3 to LC3 is regulated by phosphorylation on serine residues adjacent to the LIR motif, but the identity of the kinases responsible is not known [77]. It remains to be determined to what extent other events, such as elevated ROS, membrane depolarization, or indeed altered electron flux at the respiratory chain, modulate the BNIP3/NIX structure to induce interactions with LC3 or other proteins involved in mitophagy.Figure 2

Fig2: BNIP/NIX promotes mitophagy through direct interaction with LC3 at the phagophore. BNIP3 and NIX are both hypoxia-inducible genes that encode molecular adaptors that promote mitophagy through interaction with processed LC3-related molecules at nascent phagophores (A). Both BNIP3 and NIX interact with Bcl-2 and Bcl-XL through their amino terminal ends, and Bcl-2/Bcl-XL has been postulated to play both positive and negative regulatory effects on BNIP3 function (A). BNip3 has also been shown to interact with regulators of mitochondrial fission (Drp-1) and mitochondrial fusion (Opa-1). These interactions are positive and negative, respectively, resulting in a role for BNIP3 in promoting fission while inhibiting fusion (B). BNIP3 has also been shown to interact with the small GTPase, Rheb, resulting in reduced Rheb activity, reduced mTOR activity, and reduced cell growth (C). This function for BNIP3 in modulating Rheb (C) contrasts with the proposed functional interaction of NIX with Rheb (D) that elicits a mTOR-independent effect on mitophagy by promoting LC3 processing and increased mitochondrial turnover in cells grown on oxidative substrates (D). NIX is required for recruitment of Rheb to mitochondria and its activating effect on mitophagy.

Mentions:
BNIP3 and NIX integrate into the OMM as redox-resistant homo-dimers with a short 10 to 11 amino acid carboxy terminal tail in the intermembrane space and a proximal 23 amino acid transmembrane domain containing a critical glycine zipper that is required for both dimerization and membrane integration [69-71]. The remaining amino terminal portion of both BNIP3 and NIX protrudes out into the cytosol where both BNIP3 and NIX interact with LC3-related molecules at associated phagophore membranes [72,73] (Figure 2A). The direct interaction of BNIP3 and NIX with processed LC3B-II or GABARAP is dependent on a LC3-interacting region (LIR) located within an unstructured amino terminal region of each protein (amino acids 15 to 21 in BNIP3 and 43 to 49 in NIX) [72-74], and thus, similar to ATG32 in yeast [75,76], BNIP3 and NIX function to target mitochondria directly to the autophagosome for degradation. Binding of BNIP3 to LC3 is regulated by phosphorylation on serine residues adjacent to the LIR motif, but the identity of the kinases responsible is not known [77]. It remains to be determined to what extent other events, such as elevated ROS, membrane depolarization, or indeed altered electron flux at the respiratory chain, modulate the BNIP3/NIX structure to induce interactions with LC3 or other proteins involved in mitophagy.Figure 2

Bottom Line:
Mitophagy is a selective form of macro-autophagy in which mitochondria are selectively targeted for degradation in autophagolysosomes.Mitophagy can have the beneficial effect of eliminating old and/or damaged mitochondria, thus maintaining the integrity of the mitochondrial pool.The challenges and opportunities that come with our heightened understanding of the role of mitophagy in cancer are reviewed here.

Affiliation:
The Ben May Department for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, IL 60637 USA ; The Committee on Cancer Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637 USA.

ABSTRACTMitophagy is a selective form of macro-autophagy in which mitochondria are selectively targeted for degradation in autophagolysosomes. Mitophagy can have the beneficial effect of eliminating old and/or damaged mitochondria, thus maintaining the integrity of the mitochondrial pool. However, mitophagy is not only limited to the turnover of dysfunctional mitochondria but also promotes reduction of overall mitochondrial mass in response to certain stresses, such as hypoxia and nutrient starvation. This prevents generation of reactive oxygen species and conserves valuable nutrients (such as oxygen) from being consumed inefficiently, thereby promoting cellular survival under conditions of energetic stress. The failure to properly modulate mitochondrial turnover in response to oncogenic stresses has been implicated both positively and negatively in tumorigenesis, while the potential of targeting mitophagy specifically as opposed to autophagy in general as a therapeutic strategy remains to be explored. The challenges and opportunities that come with our heightened understanding of the role of mitophagy in cancer are reviewed here.